Abstract

BACKGROUND. Awake neurosurgery requires patients to converse and respond to visual or verbal prompts to identify and protect brain tissue supporting essential functions such as language, primary sensory modalities, and motor function. These procedures can be poorly tolerated because of patient anxiety, yet acute anxiolytic medications typically cause sedation and impair cortical function. METHODS. In this study, direct electrical stimulation of the left dorsal anterior cingulum bundle was discovered to reliably evoke positive affect and anxiolysis without sedation in a patient with epilepsy undergoing research testing during standard inpatient intracranial electrode monitoring. These effects were quantified using subjective and objective behavioral measures, and stimulation was found to evoke robust changes in local and distant neural activity. RESULTS. The index patient ultimately required an awake craniotomy procedure to confirm safe resection margins in the treatment of her epilepsy. During the procedure, cingulum bundle stimulation enhanced positive affect and reduced the patient’s anxiety to the point that intravenous anesthetic/anxiolytic medications were discontinued and cognitive testing was completed. Behavioral responses were subsequently replicated in 2 patients with anatomically similar electrode placements localized to an approximately 1-cm span along the anterior dorsal cingulum bundle above genu of the corpus callosum. CONCLUSIONS. The current study demonstrates a robust anxiolytic response to cingulum bundle stimulation in 3 patients with epilepsy. TRIAL REGISTRATION. The current study was not affiliated with any formal clinical trial. FUNDING. This project was supported by the American Foundation for Suicide Prevention and the NIH.

Figure 4

(A) Top: LFP shows reduced power in decibels (dB) of an endogenous cingulum oscillation of 6 to 11 Hz following stimulation (blue) compared with prestimulus baseline (gray), but not following nonstimulated sham (green). Bottom: Ten natural (unstimulated) social smiles were analyzed during intracranial recording. The endogenous oscillation of 6 to 11 Hz was again observed in the naturalistic data set at the pre-smile baseline (gray) and following sham LFP epochs in which smiling was not present (green) and showed no evidence of reduced power associated with natural smiling (blue). Lighter-colored areas indicate 95% CIs generated by a random reshuffling procedure. (B) LFP shows distinct reduction in power across the recorded lateral-opercular frontal-parietal lobe network (including ipsilateral motor and sensory cortices of the head and face) following stimulation, but not following sham stimulation or unstimulated natural smiles. Ventral ACC, amygdala, parahippocampus, and medial precuneus showed increased in 6- to 11-Hz power (increased synchrony) following cingulum stimulation. (C) After stimulation, LFP likewise showed reduced network coherence between the cingulum and multiple contacts corresponding to the ipsilateral motor/sensory cortices of the head/face, but not following sham stimulation or unstimulated natural smiles. For B and C, the colored dots indicate electrode locations and the corresponding power, using the heatmap as indicated in the legend. Only contacts with statistically significant changes in power or coherence are presented with colored dots; gray dots indicate contact locations with nonsignificant changes in power or coherence. Statistical significance reflects the percentile of the null (random) distribution at which the actual value was observed. For more precise colocalization of significant contacts within the anatomic MRI, see Supplemental Figures 2 and 3.